As our society grows progressively older, age-related memory loss is posing an increasing problem, not only for quality of life of elderly people, but also for relatives, caregivers and the health care system in general. While the biological mechanisms of cognitive decline are poorly understood, both environmental and genetic factors are known to contribute. It is therefore important to understand how the brain and one of its major functions, i.e. memory, age during human life and identify specific biochemical targets and mechanisms that are associated with age-related impairment of learning and memory. Neuropeptide S (NPS) is a recently identified transmitter in the brain. NPS produces arousal and wakefulness and reduces behavioral signs of anxiety in rodents. Recent studies in our lab demonstrate that NPS can potently enhance learning and memory. A naturally occurring mutation in the human NPS receptor gene changes the sensitivity of the receptor significantly, which may have a behavioral impact on memory. These evidences make the NPS system an interesting candidate for development of new drugs with pro-cognitive effects that can help to alleviate symptoms of age-related memory decline. The first part of this proposal will test the effects of NPS on memory formation in very old mice, which are an established model to study age-related memory deficits. Since NPS can enhance memory formation in young mice, we expect to see similar effects in aged mice. Second, we will analyze the pharmacology and signal transduction of a number of naturally occurring variants of the human NPS receptor in order to identify particular versions of the gene that respond differently to activation by NPS. Since these mutations in the NPS receptor occur with high frequency in the human population, we will next address the question whether different forms of the receptor may contribute to age-related cognitive decline or exert a protective function. For this part of the study, we will analyze NPS receptor genotypes in participants of a very large geriatric study: the "90+ Study". We will specifically test whether more sensitive or attenuated NPS receptor gene variants are associated with memory performance, onset and progression of memory decline, or other mental capabilities in these oldest-old members of our society (over 90 years old at time of enrollment). Together, we intend to validate the NPS system as a novel drug target for treatment of age-related cognitive decline. Results from these studies will greatly advance our knowledge about neural mechanisms underlying cognitive aging. PUBLIC HEALTH RELEVANCE: Age-related cognitive decline is a tremendous burden for affected individuals, society, and the health care system, while the underlying neurobiological mechanisms remain largely unknown. In the current proposal, we plan to use translational animal models, in vitro pharmacology, and human molecular genetic tools to explore the potential of the Neuropeptide S system as an emerging target for treatment of age-related cognitive decline. Analyzing naturally occurring polymorphisms in the human NPS receptor gene that are associated with cognitive performance may have practical implications to assess individual risk for developing cognitive decline that would warrant early prevention. The study is both exploratory and translational and could lead to a better understanding of neural mechanisms underlying cognitive aging.